[Clinical features, diagnostics and treatment of FGF23 secreting tumors: series of 40 clinical cases].

INTRODUCTION: Tumor-induced osteomalacia is an acquired rare disease manifested by hypophosphatemic osteomalacia due to excessive secretion of fibroblast growth factor 23 (FGF23). FGF 23 is a non-classical hormone secreted by bone tissue (osteocytes) and regulates phosphorus metabolism.The aim of this work is to present clinical experience in the diagnosis, treatment and rehabilitation of patients with tumor-induced osteomalacia. MATERIALS AND METHODS: 40 patients with clinically-confirmed tumor-induced osteomalacia were included in the study, 34 of whom had the tumor localized, 27 underwent surgical treatment and 21 achieved stable remission. RESULTS: The median age was 48 [41; 63] years, 43% were men, the time left from the the onset of the disease was 8 [4; 10] years. Biochemical findings were hypophosphatemia 0.47 [0.4; 0.53] mmol/l, a decrease in the tubular reabsorption phosphate 62 [52; 67]%, and an increase in alkaline phosphatase of 183 [112; 294] units/l. At the time of diagnosis, 100% had multiple pathological fractures, only 10% could move independently, and 77.5% classified the pain as unbearable (8-10 points according to the 10-point pain syndrome scale ). Among the methods used to detect tumors, the most sensitive were scintigraphy with tectrotide with SPECT/CT 71.4% (20/28) and MRI 90% (18/20). In 35% of cases, the tumor was localized in soft tissues and in 65% in bone tissue; The tumor was most often detected in the lower extremities, followed by the head in frequency of localization. 18 patients currently have no remission and they receive conservative treatment (phosphorus and alfacalcidol n=15 and burosumab n=3). In case of achieving remission (n=21), regression of clinical symptoms and restoration of bone and muscle mass was observed. Extensive excision of the tumor without prior biopsy resulted in the best percentage of remission - 87%. CONCLUSION: Tumor-induced osteomalacia is characterized by severe damage to bone and muscle tissue with the development of multiple fractures, muscle weakness and severe pain syndrome. In laboratory diagnostics, attention should be paid to hypophosphatemia, a decrease in the tubular reabsorption phosphate index and increased alkaline phosphatase. The use of functional diagnostic methods with a labeled somatostatin analogue to the subtype 2 receptor and MRI with contrast enhancement are the most accurate methods of topical diagnostics. In case of localization of the tumor, a wide excision without a preliminary biopsy is recommended.

Early Postoperative Serum Phosphate Drop Predicts Sufficient Hypertrophy After Liver Surgery.

OBJECTIVE: The aim of this study was to assess the impact of postoperative hypophosphatemia on liver regeneration after major liver surgery in the scenario of Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) and living liver donation (LLD). BACKGROUND: Hypophosphatemia has been described to reflect the metabolic demands of regenerating hepatocytes. Both ALPPS and LLD are characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia. METHODS: Serum phosphate changes within the first 7 postoperative days after ALPPS (n=61) and LLD (n=54) were prospectively assessed and correlated with standardized volumetry after 1 week. In a translational approach, postoperative phosphate changes were investigated in mice and in vitro . RESULTS: After ALPPS stage 1 and LLD, serum phosphate levels significantly dropped from a preoperative median of 1.08 mmol/L [interquartile range (IQR) 0.92-1.23] and 1.07 mmol/L (IQR 0.91-1.21) to a postoperative median nadir of 0.68 and 0.52 mmol/L, respectively. A pronounced phosphate drop correlated well with increased liver hypertrophy ( P <0.001). Patients with a low drop of phosphate showed a higher incidence of posthepatectomy liver failure after ALPPS (7% vs 31%, P =0.041). Like in humans, phosphate drop correlated significantly with degree of hypertrophy in murine ALPPS and hepatectomy models ( P <0.001). Blocking phosphate transporter (Slc20a1) inhibited cellular phosphate uptake and hepatocyte proliferation in vitro. CONCLUSION: Phosphate drop after hepatectomy is a direct surrogate marker for liver hypertrophy. Perioperative implementation of serum phosphate analysis has the potential to detect patients with insufficient regenerative capacity at an early stage.

Occipital bone and tumor-induced osteomalacia: a rare tumor site for an uncommon paraneoplastic syndrome.

INTRODUCTION: Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome due to the overproduction of fibroblast growth factor 23 (FGF23). It is predominantly caused by mesenchymal tumors and cured upon their complete removal. Non-surgical treatment is an alternative option but limited to specific clinical conditions. METHODS: We report a challenging case of TIO caused by a tumor involving the occipital bone. We also performed a literature review of TIO caused by tumors localized at this site, focusing on clinical findings, treatment, and outcomes. RESULTS: The patient, a 62-year-old male, presented with a long-lasting history of progressive weakness. Biochemical evaluation revealed severe hypophosphatemia due to low renal tubular reabsorption of phosphate with raised intact FGF23 values. A 68 Ga-DOTATATE PET/TC imaging showed a suspicious lesion located in the left occipital bone that MRI and selective venous catheterization confirmed to be the cause of TIO. Stereotactic gamma knife radiosurgery was carried out, but unfortunately, the patient died of acute respiratory failure. To date, only seven additional cases of TIO have been associated to tumors located in the occipital bone. Furthermore, the tumor involved the left side of the occipital bone in all these patients. CONCLUSION: The occipital region is a difficult area to access so a multidisciplinary approach for their treatment is required. If anatomical differences could be the basis for the predilection of the left side of the occipital bone, it remains to be clarified.

Total hip arthroplasty for treatment of femoral neck fracture due to hypophosphatemic osteomalacia: a retrospective case series with mean follow-up of five years.

BACKGROUND: To retrospectively characterize the clinical characteristics and efficacy of total hip arthroplasty and the important factors needing attention in hypophosphatemic osteomalacia (HO) patients with hip involvement. PATIENTS AND METHODS: We performed a review of seven patients (two women and five men) referred to our clinic with a final diagnosis of HO who received total hip arthroplasty between 2010 and 2018. Five patients (Group 1) received proper medical management with or without aetiologic therapy, while the other two patients (Group 2) did not receive due to misdiagnosis. The mean follow-up duration was 5.1 ± 2.0 years. RESULTS: The patients in Group 1 had significant relief of pain and improved laboratory results. The mean Harris Hip Score of Group 1 increased from 44.2 ± 6.0 to 94.0 ± 3.0, and the mean VAS score decreased from 8.8 ± 0.4 to 1.8 ± 0.7. However, the progressive extensive pain score in Group 2 had no obvious improvement, with the Harris Hip Score increasing from 45.5 ± 0.5 to 60 ± 28.0 and the VAS score decreasing from 9.0 ± 1.0 to 6.5 ± 2.5. CONCLUSION: THA appears to be an effective method for hip arthritis or joint deformities resulting from hypophosphatemic osteomalacia. A satisfactory outcome of the surgery depends on the early etiological identification, the treatment of hypophosphatemia, a careful operation, and the operative strategies, as well as proper medical treatment.

Tumor-induced hypophosphatemic osteomalacia caused by a mesenchymal tumor of the mandible managed by a segmental mandibulectomy and microvascular reconstruction with a free fibula flap.

BACKGROUND: Tumor-induced osteomalacia is a rare paraneoplastic syndrome in which patients develop hypophosphatemia and osteomalacia. METHODS AND RESULTS: Here, we report a unique case of a 42-year-old man who presented to our institution with a 1-year history of pain in his ribs, hips, lower back, and feet. Radiologic examination revealed a decrease in bone density and multiple insufficiency fractures. Laboratory evaluation revealed hypophosphatemia, low serum 1,25 dihydroxy vitamin D3 , and elevated fibroblast growth factor 23 (FGF23). A positron emission tomography/CT scan showed increased uptake in the right mandibular third molar region. Panoramic radiography and CT scanning showed a lytic expansile bone lesion. A mandibular bone biopsy revealed a mixed connective tissue tumor. A right segmental mandibulectomy was performed, followed by microvascular reconstruction. The resection was confirmed by normalization of serum phosphate and FGF23. CONCLUSION: Successful management of this condition was achieved, with complete surgical resection of the tumor and reconstructive surgery.

Treatment and outcomes of tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors: retrospective review of 12 patients.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. Nonspecific symptoms make the diagnosis elusive. In addition, locating the responsible tumor(s) is challenging. The aim of this study was to investigate the clinical management and outcomes of TIO. METHODS: The clinical features, diagnostic procedures, treatment, and outcomes of 12 patients were reviewed retrospectively. RESULTS: The cohort comprised six men and six women (mean age 45.5 ± 9.9 years, range 23-61 years). The mean duration of disease was 3.7 ± 2.6 years. All patients manifested progressive bone pain, muscle weakness, and/or difficulty walking. Serum phosphorus concentrations were low in all patients (mean 0.42 ± 0.12 mmol/L). Technetium-99m octreotide scintigraphy was performed in 11 patients and showed lesions in the right distal femur, left femoral head, and right tibial plateau, respectively, in three patients. Magnetic resonance imaging (MRI) was negative for lesions in one patient. Two patients underwent biopsies that showed negative histopathology. Two patients, at 2 years and 8 months, respectively, after having negative technetium-99m octreotide studies, underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT), which revealed lesions in the sacrum and soft tissue of the left palm, respectively. One tumor was detected by CT and MRI. Overall, lesion sites were the head (two patients, 16.7%), thoracic and lumbar region (two, 16.7%), pelvis (three, 25%), lower limbs (four, 33.3%), and upper limbs (one, 8.3%). All patients underwent surgery, and histopathology showed phosphaturic mesenchymal tumors in each. Postoperatively, serum phosphorus concentrations normalized within 2-7 days in 11 patients. With follow-ups of 1-41 months, surgery was effective in 10 patients. One patient developed local recurrence and another had metastases. CONCLUSIONS: Locating tumors responsible for tumor-induced osteomalacia is often challenging. Although complete tumor resection confers a good prognosis in most patients, surveillance for recurrence and metastasis is necessary. Before surgery or when surgery is not indicated, oral phosphate can alleviate symptoms and metabolic imbalance.

A rare case of multiple phosphaturic mesenchymal tumors along a tendon sheath inducing osteomalacia.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia, reduction of 1,25-dihydroxyl vitamin D, and bone calcification disorders. Tumors associated with TIO are typically phosphaturic mesenchymal tumors that are bone and soft tissue origin and often present as a solitary tumor. The high production of fibroblast growth factor 23 (FGF23) by the tumor is believed to be the causative factor responsible for the impaired renal tubular phosphate reabsorption, hypophosphatemia and osteomalacia. Complete removal of the tumors by surgery is the most effective procedure for treatment. Identification of the tumors by advanced imaging techniques is difficult because TIO is small and exist within bone and soft tissue. However, systemic venous sampling has been frequently reported to be useful for diagnosing TIO patients. CASE PRESENTATION: We experienced a case of 39-year-old male with diffuse bone pain and multiple fragility fractures caused by multiple FGF23-secreting tumors found in the hallux. Laboratory testing showed hypophosphatemia due to renal phosphate wasting and high levels of serum FGF23. Contrast-enhanced MRI showed three soft tissue tumors and an intraosseous tumor located in the right hallux. Systemic venous sampling of FGF23 revealed an elevation in the right common iliac vein and external iliac vein, which suggested that the tumors in the right hallux were responsible for overproduction of FGF23. Thereafter, these tumors were surgically removed and subjected to histopathological examinations. The three soft tissue tumors were diagnosed as phosphaturic mesenchymal tumors, which are known to be responsible for TIO. The fourth tumor had no tumor structure and was consisting of hyaline cartilage and bone tissue. Immediately after surgery, we noted a sharply decrease in serum level of FGF23, associated with an improved hypophosphatemia and a gradual relief of systematic pain that disappeared within two months of surgery. CONCLUSION: The authors reported an unusual case of osteomalacia induced by multiple phosphaturic mesenchymal tumors located in the hallux. Definition of tumors localization by systemic venous sampling led to successful treatment and cure this patient. The presence of osteochondral tissues in the intraosseous tumor might be developed from undifferentiated mesenchymal cells due to high level of FGF23 produced by phosphaturic mesenchymal tumors.

Tumor(s) induced osteomalacia--a curious case of double trouble.

CONTEXT: We report a case of tumor-induced osteomalacia with evidence of synchronous multifocal fibroblast growth factor 23 (FGF23) production. OBJECTIVE: The aim is to present a case of tumor-induced osteomalacia and to highlight the fact that incomplete removal of multifocal FGF23-producing tumors, which are not entirely picked up by functional imaging, could be the cause of treatment failure. SETTING: The patient was treated in the Department of Endocrinology of a tertiary care center in India. PATIENT: We report the case of a 42-year-old male with tumor-induced osteomalacia. INTERVENTION: We treated the tumor-induced osteomalacia with staged surgery of the two tumors. The 18F-fluorodeoxyglucose (FDG)-avid lesion (considered the sole culprit lesion after functional imaging) was resected first, followed by the non-FDG-avid lesion. The sequential removal of both tumors resulted in complete cure. RESULTS: The patient had hypophosphatemia and hyperphosphaturia. C-Terminal FGF23 level was elevated. Positron emission tomography-computed tomography showed two lesions-an FDG-avid lesion in the right leg, and a non-avid lesion in the left thigh. After removal of the FDG-avid lesion, the hypophosphatemia persisted, and the FGF23 level showed only modest reduction. The patient had complete clinical and biochemical resolution only after removal of the second non-FDG-avid tumor. CONCLUSIONS: We present the case of a tumor-induced osteomalacia whose biochemical parameters did not improve after removal of the FDG-avid tumor initially. The possibility of multifocal FGF23 production was considered, and the second, non-FDG-avid lesion was resected, which resulted in complete cure. Thorough clinical examination and meticulous follow-up with documentation of the biochemical resolution are necessary for management of all patients with this rare disorder.

Deliberate total parathyroidectomy: a potentially novel therapy for tumor-induced hypophosphatemic osteomalacia.

BACKGROUND: Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic metabolic bone disorder that can be cured by removing or ablating the offending tumor. However, when the tumor cannot be localized, lifelong therapy with oral phosphate and calcitriol or cinacalcet with close monitoring is required. CASE REPORT: A 56-year-old man was diagnosed with TIO in 1990. Initial therapy consisted of oral phosphate and calcitriol with symptomatic and biochemical improvement and healing of osteomalacia. Eight years later, hypercalcemic hyperparathyroidism developed, requiring subtotal parathyroidectomy with a transient increase in serum phosphate and normalization of serum calcium and PTH. Recurrent hypercalcemic hyperparathyroidism developed after 10 years of medical therapy. A deliberate total parathyroidectomy produced a prompt rise in serum phosphate into the normal range > 3.0 mg/dL and remained normal during the next 4 years of follow-up, despite continued very high serum fibroblast growth factor-23 levels throughout the 23-year follow-up. CONCLUSION: We report an unusual case of a TIO patient with long-term follow-up who developed recurrent hypercalcemic hyperparathyroidism on long-term oral phosphate therapy. Deliberate total parathyroidectomy normalized serum phosphate despite persistently elevated fibroblast growth factor-23 levels. Total parathyroidectomy offers a potentially novel therapy in some patients with TIO in whom medical therapy is not feasible or the tumor is unresectable.

Clinical manifestations of hypercalcemia and hypophosphatemia after kidney transplantation.

INTRODUCTION: Abnormalities of calcium and phosphorus metabolism in end-stage renal disease patients can persist after transplantation. We investigated their natural courses after transplantation, their risk factors for posttransplantation hypercalcemia and hypophosphatemia, and their impacts on allograft outcomes. METHODS: We retrospectively analyzed a total of 490 adult patients who underwent kidney transplantations between 2000 and 2009. RESULTS: The serum calcium continued to increase, and reaching a plateau at around 3 months after transplantation. Thereafter it decreased, reaching a stable level by 2 years. Forty-four patients (9.0%) displayed hypercalcemia within 1 year; it persisted longer than that in 23 subjects (4.7%). Both longer dialysis duration (odds ratio [OR] 1.423; 95% confidence interval [CI], 1.192-1.699) and high intact serum parathyroid hormone (iPTH) level before transplantation (OR 1.002; 95% CI, 1.000-1.003) increased the risk for posttransplantation hypercalcemia. After a significant decrease during the first week, the serum phosphorus level increased, becoming stable between 1 and 6 months after transplantation. Hypophsphatemia occurred in 379 patients (77.3%) with 336 patients displaying hypophosphatemia without hypercalcemia. However, neither hypercalcemia nor hypophosphatemia influenced graft outcomes. Eight patients underwent pretransplantation parathyroidectomy, whereas 4 patients underwent posttransplantation parathyroidectomy. Neither group of patients experienced posttransplantation hypercalcemia. CONCLUSIONS: Both hypercalcemia and hypophosphatemia are common after renal transplantation, especially among patients with a long history of dialysis before transplantation. Strict control of hyperparathyroidism including parathyroidectomy before transplantation may be the appropriate approach to these abnormalities.

Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature.

Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.

[Hypophosphatemic diabetes and knee pain: does treatment with total knee arthroplasty promise success?]. / Phosphatdiabetes und Knieschmerz: Ist die Versorgung mit einer Knietotalendoprothese erfolgversprechend?

Hypophosphatemic diabetes, a rare metabolic disease, presents in children, young adults as well as in elderly patients. In this report we describe the case of a 43-year-old woman with known hypophosphatemic diabetes who complained of severe knee pain after several osteotomies of the lower extremities. The patient was treated with bilateral total knee arthroplasty. The immediate post-operative outcome was good but showed deterioration at 12-month follow-up with decreased range of motion due to ligament stiffness. Knee arthroplasty in patients with hypophosphatemic diabetes remains a challenge for the orthopaedic surgeon. Arthroplasty can be recommended in severe knee pain; however, pre-operative interventions should be considered to prevent post-operative complications.

Biologic characteristics of mesenchymal stromal cells and their clinical applications in pediatric patients.

In the past few years, intensive research in the understanding of the biologic characteristics of the mesenchymal stromal cells has already led to some early clinical applications. The aim of this review is to summarize the latest information from basic science advances and the outcome of their use in clinical practice with a particular focus in pediatric patients. The minimum criteria required to identify mesenchymal stromal cells, their immunosuppressive-nonimmunogenic properties and their attribution in the treatment of graft-versus-host disease, in the acceleration of hematopoietic recovery, in tissue repair/tissue engineering and in the treatment of selected inherited disorders are discussed. Appropriate preclinical models, completion of ongoing and development of new clinical trials will establish the role of these cells in the treatment of both adult and pediatric patients.

Central pontine myelinolysis induced by hypophosphatemia following Wernicke's encephalopathy.

A 62-year-old woman, after a resection and ileostomy for multiple perforations of the terminal ileum and prolonged postoperative parenteral nutrition, developed thiamine deficiency with clinical and magnetic resonance imaging features of Wernicke's disease. Later on the patient developed central pontine myelinolysis. For this condition, a pathogenetic role of a transient hypophosphatemia was suggested by both laboratory data and course of the disease.

[Reversion of hypophosphatemia after the excision of a composite hemangioendothelioma in the great toe]. / Hipofosfatemia revertida al extirpar hemangioendotelioma compuesto del dedo mayor del pie.

We report a 43 years old male admitted to the hospital for progressive lumbar pain, lasting 20 years, that caused severe disability. On admission the patient had a serum phosphate of 2 mg/dl, an urine phosphate excretion over 300 mg/dl and serum alkaline phosphatases over 750 U/L. Serum intact parathormone was normal and tubular maximum phosphorus/glomerular filtration was 0.7 mg/dl. Bone scintigraphy showed an increased radionuclide uptake in condro-costal joints. Bone densitometry showed femoral osteoporosis. A violet colored mass was detected in a great toe. It was removed and the pathological diagnosis was a composite hemangioendothelioma. After tumor excision, serum phosphate levels returned to normal values and symptoms disappeared within 15 days.

Hipofosfatemia revertida al extirpar hemangioendotelioma compuesto del dedo mayor del pie / Reversion of hypophosphatemia after the excision of a composite hemangioendothelioma in the great toe

We report a 43 years old male admitted to the hospital for progressive lumbar pain, lasting 20 years, that caused severe disability. On admission the patient had a serum phosphate of 2 mg/dl, an urine phosphate excretion over 300 mg/dl and serum alkaline phosphatases over 750 U/L. Serum intact parathormone was normal and tubular maximum phosphorus/glomerular filtration was 0.7 mg/dl. Bone scintigraphy showed an increased radionuclide uptake in condro-costal joints. Bone densitometry showed femoral osteoporosis. A violet colored mass was detected in a great toe. It was removed and the pathological diagnosis was a composite hemangioendothelioma. After tumor excision, serum phosphate levels returned to normal values and symptoms disappeared within 15 days.